Process for the preparation of 2-hydroxyalkyl halophenones

ABSTRACT

A process is provided for the preparation of compounds of Formula (1):                    
     wherein X 1  and X 2  are each independently H, Cl or F, provided that at least one of X 1  and X 2  is Cl or F; one of R 1  and R 2  is H and the other is OH; and R 5  is an unsubstituted alkyl, preferably a C 1-6  alkyl, group. The process comprises condensing a 2-chloroalkanoic acid with an optionally substituted benzyl alcohol to form a 2-(optionally substituted benzyloxy) alkanoic acid, converting the condensation product to the corresponding acid chloride and then either reacting the acid chloride with a compound of the Formula (2) in the presence of a source of copper (I) to give a compound of Formula (3) wherein one of R 3  and R 4  is H and the other is optionally substituted benzyloxy;                    
     or reacting the acid chloride with a compound of Formula (4): 
     
       
         A—NH—B 
       
     
     wherein A and B independently represent substituted alkyl, alkoxy, aryl or oxyaryl groups, or are linked to form a heterocyclic ring to form an amide, and then reacting the amide with a compound of Formula (2) to give a compound of Formula (3). The optionally substituted benzyl group from the compound of Formula (3) can removed by hydrogenation.

This invention relates to processes for the preparation of certainchiral compounds and to novel compounds used in the processes.

1(2,4-dihalophenyl)-2-hydroxy-1-propanones are key intermediates for thesynthesis of a variety of pharmaceuticals and agrochemicals,particularly antifungal compounds and medicines used in the treatment ofAIDS. For example Sch 42427/SM9164 and ER-30346 are made from theseintermediates.

The chiral 2-hydroxy group in these compounds has been prepared bychiral α-hydroxylation of the corresponding 2′,4′-difluoropropiophenone.One such method is described in Tetrahedron Letters, Vol 37, No. 45,pp8117-8120 (1996). An alternative method involves the regioselectivering opening of a 2′,4′-fluorophenyl propylene oxide, as described inTetrahedron Letters, Vol 35, No. 45, pp8299-8302 (1994). We have nowdevised a process for preparing 2′,4′-dihalo-2-hydroxypropiophenoneswith good enantiomeric purity from readily available L- orD-2-chloropropionic acid.

According to one aspect of the present invention there is provided aprocess for the preparation of a compound of Formula (1):

wherein:

X¹ and X² are each independently H, Cl or F, provided that at least oneof X¹ and X² is Cl or F;

one of R¹ and R² is H and the other is OH; and

R⁵ is an unsubstituted alkyl, preferably a C₁₋₆ alkyl, group comprisingthe steps:

(a) condensing a 2-chloroalkanoic acid with an optionally substitutedbenzyl alcohol to form a 2-(optionally substituted benzyloxy) alkanoicacid;

(b) converting the product from step (a) to the corresponding acidchloride; then either:

(c) reacting the product of step (b) with a compound of the Formula (2)in the presence of a source of copper (I) to give a compound of Formula(3) wherein one of R³ and R⁴ is H and the other is optionallysubstituted benzyloxy;

or

(d) reacting the product of step (b) with a compound of Formula (4):

A—NH—B

wherein A and B independently represent substituted alkyl, alkoxy, arylor oxyaryl groups, or are linked to form a heterocyclic ring to form anamide, and then reacting the amide with a compound of Formula (2) togive a compound of Formula (3); and

(e) removing the optionally substituted benzyl group from the compoundof Formula (3) by hydrogenation, thereby giving the compound of Formula(1).

The process steps a) to d) above for the production of a compound ofFormula (3) form another aspect of the present invention.

In step (a) the reaction of the 2-chloroalkanoic acid with an optionallysubstituted benzyl alcohol proceeds with an inversion of configuration.Accordingly, the choice of which enantiomer of the 2-chloroalkanoic acidwill be made on the basis of the desired configuration of the desiredcompound of Formula (1) or Formula (3). 2-chloroalkanoic acids which canbe employed in the present invention have the general formula:R⁵—CR⁶R⁷—CO₂H, wherein R⁵ is an alkyl group, preferably a C₁₋₆ alkylgroup, and most preferably a methyl group, and one of R⁶ or R⁷ is Cl,the other being H. The most preferred 2-chloroalkanoic acids are L- andD-2-chloropropionic acid.

The optionally substituted benzyl alcohol is preferably benzyl alcoholor a benzyl alcohol having from 1 to 5 substituents, often selected fromthe group consisting of halo, preferably F, Cl or Br; nitro; C₁₋₄-alkyl,preferably methyl or ethyl; C₁₋₄-alkoxy, preferably methoxy or ethoxy;carboxy; sulpho and amino. Benzyl alcohol is most preferred.

The condensation in step (a) is preferably performed in the presence ofa strong base, preferably an inorganic base. Examples of suitableorganic bases include alkyl lithium salts such as butyl lithium, andalkali metal, especially lithium, alkylamide salts such as lithiumdiisopropylamide. Examples of suitable inorganic bases include alkalimetals, especially lithium, sodium and potassium metal, alkali metalhydrides such as lithium, sodium or potassium hydride, alkali metalhydroxides, carbonates and bicarbonates, especially sodium hydroxide,potassium hydroxide and mixtures thereof.

The condensation of step (a) is preferably performed at an elevatedtemperature, more preferably 30° C. to 150° C., especially 40° C. to120° C.

Condensation step (a) can be performed in the presence of an organicsolvent which is unreactive towards the reagents employed. Examples ofsuitable solvents include halocarbons, especially chlorocarbons such asdichloromethane, chloroform, dichloroethane, chlorobenzene, and ethers,particularly C₁₋₆ alkylethers such as t-butyl methyl ether andtetrahydrofuran. It is preferred that the benzyl alcohol serves as itsown solvent, and in many embodiments, a molar excess of benzyl alcoholover the chloropropionic acid is employed, such as a mole ratio ofbenzyl alcohol to 2-chloroalkanoic acid of from 2:1 to 15:1, andcommonly from 5:1 to 10:1.

Conversion of the product of step (a) to the corresponding acid chloride(i.e. —COCl) is preferably performed using oxalyl chloride, thionylchloride, or a phosphorus halide, such as PCL₃ or PCL₅. Elevatedtemperatures are preferred, especially 30° C. to 110° C., morepreferably 35° C. to 90° C. The reaction is commonly carried out neat,but an organic solvent which is unreactive towards the reagents may beemployed. Examples of suitable solvents include halocarbons, especiallychlorocarbons such as dichloromethane, chloroform, dichloroethane,chlorobenzene; ethers, particularly C₁₋₆ alkylethers such as t-butylmethyl ether and tetrahydrofuran; and aromatic solvents such as toluene.

The source of copper (I) used in step (c) is preferably a Cu (I) salt,such as CuNO₃, CuCN or a copper (I) halide, especially CuCl, CuBr orCul. The amount of copper (I) source used is preferably between 80 and200 mole % relative to the number of moles of the acid chloride productof step (b), more preferably from 85 to 150 mole %, especially 90 to140mole %.

Step (c) is commonly carried out in the presence of an organic solventwhich is unreactive towards the reagents is commonly employed. Examplesof suitable organic solvents include ethers, particularly C₁₋₆alkylethers such as t-butyl methyl ether and tetrahydrofuran; andaromatic solvents such as toluene. The reaction temperature of step (c)is commonly in the range of from −78° C. to 30° C., and preferably from−40° C. to 0° C.

The compound of Formula (2) is commonly prepared by reacting theappropriately substituted phenyl bromide with magnesium metal in thepresence of a suitable solvent, often the solvent employed in step (c).Preferably, a stoichiometric ratio or moderate molar excess of phenylbromide to magnesium is employed, often a molar ratio of from 1:1 to2:1, and advantageously from 1.25:1 to 1.75:1. The preparation oftentakes place at a temperature of from ambient temperature (20-25° C.) toabout 35° C. It will be recognised that the preparation of compounds ofFormula (2) can be exothermic, and so appropriate cooling isadvantageously provided to control such exotherms.

In the amine compound of Formula (4) employed in step (d), when A or Brepresents an alkyl or alkoxy group, it is preferably a C₁₋₄ alkyl oralkoxy group, and particularly a methyl or methoxy group. When A or Brepresents an aryl or aryloxy group, it is preferably a phenyl orphenoxy group. When A and B are linked to form a ring, the ringpreferably contains from 5 to 8 members, and 1, 2 or 3 heteroatoms. Inaddition to the amine nitrogen, other heteroatoms, especially oxygen maybe present in the ring. Examples of preferred amines include morpholine,pyrrolidine and N-methoxy-N-methylamine. The amine can be employed as afree amine or in the form of a salt, especially a hydrochloride salt.The mole ratio of amine to acid chloride is commonly from 1:1 to 2:1.Step (d) is commonly carried out in the presence of an organic solventwhich is unreactive towards the reagents is commonly employed.Advantageously, the solvent employed is substantially water insoluble.Examples of suitable organic solvents include halocarbons, especiallychlorocarbons such as dichloromethane, chloroform, dichloroethane,chlorobenzene; ethers, particularly C₁₋₆ alkylethers such as t-butylmethyl ether and tetrahydrofuran; and aromatic solvents such as toluene.Step (d) is commonly carried out a temperature of from 0 to 30° C.

In step (e) the optionally substituted benzyl group can be removed bymethods known in the art, and is preferably removed from the compound ofFormula (3) by hydrogenation using a transition metal catalyst andhydrogen gas. Preferred transition metal catalysts are in group VIII ofthe periodic table, more preferably palladium, nickel and platinum, andespecially palladium on carbon, often on activated carbon. Loadings ofmetal on carbon are commonly in the range of from 1 to 20% w/w, andpreferably from about 5% to about 10% w/w. Degussa-type palladium onactivated carbon has been found to be advantageous in certainembodiments of the present invention. Solvents that can be employed inthe removal of the optionally substituted benzyl group by hydrogenationinclude alcohols, particularly C₁₋₄ alkyl alcohols; esters, particularlyesters of C₁₋₄ carboxylic acids with C₁₋₄ alcohols, preferably ethylacetate; and aromatic solvents such as toluene. Step (e) is commonlycarried out a temperature of from about 10 to 30° C., commonly atambient temperature, such as 15 to 25° C.

The compounds of Formula (3) are valuable intermediates in their ownright and generally have useful crystalline properties. This enables thecompound of Formula (3) to be crystallised thereby greatly enhancing thepurity, both chemical and particularly optical, of the desired compoundof Formula (1) and downstream pharmaceutical and agrochemical products.Furthermore, the compounds of Formula (3) are much more stable than thecorresponding free hydroxy compounds and are therefore more readilytransportable. They can also be stored for extended periods, withconversion to the corresponding free hydroxy compound being necessaryonly immediately prior to its use. Thus in a preferred embodiment theproduct of step (c) or (d) is purified by recrystallisation before step(e) is performed. Recrystallisation is preferably performed in anorganic solvent, more preferably in hydrocarbon solvent, especially alinear of branched aliphatic hydrocarbon, such as n- or iso-pentane, n-or iso-hexane, cyclohexane and petroleum fractions.

Accordingly the present invention also provides compounds of Formula (3)wherein X¹ and X² are each independently H, Cl or F, provided that atleast one of X¹ and X² is Cl or F; one of R³ and R⁴ is H and the otheris optionally substituted benzyloxy; and R⁵ is an unsubstituted alkyl,preferably a C₁₋₆ alkyl, group. Preferably, both of X¹ and X² representCl or F, and especially both are F. The benzyloxy group is oftenunsubstituted. R⁵ is most commonly a methyl group.

The process for the production of compounds of Formula (3) preferablycomprises the further step of purifying the compound of Formula (3) byrecrystallisation from an organic solvent, more preferably from one ofthe organic solvents mentioned above in the recrystallisation processfor purifying the products of steps (c) and (d).

The invention is further illustrated without limitation by the followingexamples in which all parts and percentages are by weight unlessspecified otherwise and % Str. is percent strength.

EXAMPLE 1

L-2-chloropropionic acid D-2-(benzyloxy)propionic acid

Sodium metal (34.5 g, 1.5 moles) was added in small portions withcooling to benzyl alcohol (440 g, 4.1 moles). The mixture was stirred at80°-90° C. for 2 hours, cooled to 55° C. and L-2-chloropropionic acid(68.6 g, 0.63 moles) was added over about 1 hour. The mixture wasstirred at 55° C. until gas chromatography indicated that thecondensation was complete (about 2 hours). Water (350ml) was added andthe pH was adjusted to 6.5 using concentrated HCl. Tert-butyl methylether (“TBME”, 250 ml) was added, the mixture was stirred for 5 minutesand then allowed to settle. Water (150 ml) and TBME (250 ml) were added.The aqueous layer was removed and washed with TBME (500 ml and 3×250 mlwashings). The washed, aqueous layer was then acidified to pH 1.5 usingconcentrated HCl to liberate the desired product and the product wasextracted with TBME (2×250 ml). The combined 500 ml of TBME was washedwith water (200 ml) and the solvent removed in vacuo at 50° C., 300 mmHgpressure to give the desired D-2-(benzyloxy)propionic acid (96.1 g,84%).

D-2-(benzyloxy)propionic acid D-2-(benzyloxy)propionyl chloride

Oxalyl chloride (112 g, 0.88 moles) was added dropwise at 20° C. to theproduct of stage (a) (102.86 g, 0.57 moles). The temperature roserapidly to 35° C. When the exotherm had ceased the mixture was heated to45-50° C. and the remainder of the oxalyl chloride was added at thistemperature over 45 minutes. After stirring the mixture at 50-55° C. for1.5 hours the temperature was increased to 105° C. with a nitrogensparge to remove any residual oxalyl chloride. The desiredD-2-(benzyloxy)propionyl chloride was obtained as an oil (109.7 g,94.9%).

An aliquot (ca. 5-10 ml) of a solution of 2,4-Difluorobromobenzene(98.49 g, 0.5 moles) in tetrahydrofuran (“THF”) (75 ml) was added to astirred mixture of Mg turnings (12.25 g, 0.51 moles) in THF (340 ml) atambient temperature. After 35 minutes stirring at ambient temperaturethe reaction initiated. When the temperature reached 27° C. an ice/waterbath was used to cool the reaction mixture but the temperature stillreached 50° C. before the exotherm subsided. The mixture was cooled to25° C. and the remainder of the solution of bromodifluorobenzene/THFsolution added to the Mg/THF solution with cooling over 0.5 h at 20-30°C. The mixture was stirred for a further 1.5 hours, CuCl (56.5 g, 0.57moles, dried at 110° C. for 17 hours) was added over 20 minutes at20-30° C. (ice bath cooling) and the mixture stirred for a further 1.5hours at 20-300° C. The mixture was cooled to −30° C. and the acidchloride added over 20 minutes at −25 ° to 30° C. The mixture was thenallowed to warm to room temperature and monitored by GC. After stirringovernight (17 hours), 5% GC area of the acid chloride still remained.200 ml of 18% HCl was added, keeping the temperature below 30° C. Thisacid dissolved almost all the solids apart from some residual CuCl. TBME(250 ml) was added and the mixture stirred for 10 mins. The two darkphases separated well and the aqueous phase was removed (120 ml). To theorganic was added further TBME (100 ml) and the organic-washed with 18%HCl (100 ml). Water (100 ml) was added and an emulsion was produced. Themixture was shaken and allowed to settle. A good separation thenresulted. The aqueous was removed (240 ml). The organic extract wassequentially washed with 3×18% HCl (200 ml) (in each case more than 200ml aqueous was removed) washes and then a water wash (200 ml). The waterwash resulted in a precipitate in the organic phase. To the mixture(containing the water wash) was added conc. HCl (50 ml). The mixture wasshaken then settled to give 2 phases. The aqueous was removed and theorganic diluted with further TBME (250 ml) was washed with water (150ml). An emulsion resulted and conc. HCl (50 ml) was added. The emulsioncleared to give two phases. The aqueous was removed and the organicwashed with water (2×500 ml). Some solids were apparent in the aqueousphase and these were removed with the aqueous washings. The organic wasthen washed with 9% HCl (200 ml), water (200 ml), 5% sodium carbonate(200 ml) and water (200 ml). The solvent was removed in vacuo at 60°C./20 mmHg to give the above product (3′) as a brown oil.

Hydrogen gas was bubbled through a solution of (3′) (2 g, 0.0072 moles)in methanol (50 ml) in the presence of a catalyst (5% Pd on carbon, 0.2g at 50% water content, Degussa Type E101). When gas chromatographyshowed the reaction had gone to completion the catalyst was removed byfiltration under nitrogen and methanol removed in vacuo to give (1′) asan oil (1.3 g, 95%).

EXAMPLE 2

(i) Preparation of morpholine amide 100% Mole Material Source % Str.Weight (g) Wt. (g) MWt. Moles ratio D-2-benzyl- 92 41.71 38.37 198.50.193 1 oxypropionyl chloride Morpholine Aldrich 99+ 33.96 33.62  87.10.386 2 Dichloro- Fisons 88 + 88 ml methane Water 100 ml + 100 ml

D-2-benzyloxypropionyl chloride, prepared by the method of Example 1,stages (i) and (ii), was dissolved in dichloromethane (88 ml) and cooled(0-10° C.). Morpholine was dissolved in dichloromethane (88 ml) andadded to the solution of D-2-benzyloxypropionyl chloride indichloromethane keeping the temperature between 0-10° C. The additiontook 25 minutes and a white precipitate formed. The reaction was stirredfor two hours at ca. 25° C. Water was added and the lower organic layerwas recovered and then washed with water. The organic phase wasconcentrated to give an oil (48.5 g, 96% yield).

(ii) Preparation of stock solution of Grignard:2,4-difluorophenylmagensium bromide 100% Mole Material Source % Str.Weight (g) Wt. (g) MWt. Moles ratio Mg turnings Aldrich 98 2.78 2.72  240.113 1.05 2,4- Aldrich 99+ 21.27 20.8 193 0.108 1   difluorobromobenzene THF Fisons 66 ml

The magnesium was added to the minimum amount of THF (10 ml) required tocover the metal. The 2,4-difluorobromobenzene was dissolved in thebalance of the THF (56 ml). Approximately 5 ml of this solution wascharged to the slurry of Mg/THF. Initiation occurred after 5 minutes asseen by an exotherm which reached 50° C. before cooling was applied toreturn the temperature to 30° C. The balance of the2,4-difluorobromobenzene solution was added over 30 minutes keeping thetemperature at 25-35° C. The mixture was stirred for 2-2.5 hours at30-35° C. The total volume was about 66 ml making the solution ˜1.6Massuming complete reaction.

(iii) Reaction of morpholine amide with Grignard 100% Mole MaterialSource % Str. Weight (g) Wt. (g) MWt. Moles ratio Morpholine Ex. 2(i) 9520 19 249 0.076 1 amide 2,4-difluoro Ex. 2(ii) 55 ml + 0.088 1.15 +phenyl extra extra as magnesium based required bromide on GC THF Fisons50 ml 1N HCl Rimon 200 ml 0.2  2.63 Ethyl acetate Fisons 50 ml

The morpholine amide was dissolved in the THF. The solution of Grignardwas added over 20 minutes at 20-30° C. (required slight cooling). Thereaction was stirred for 1 hour and sampled by GC. The % conversion wasused to calculate an additional charge of Grignard. The additionalGrignard was added and the reaction was stirred for 1 hour. The reactionmixture was poured into aq. 1N HCl at 20-30° C. (required slightcooling). The mixture was extracted with ethyl acetate. The upperorganic layer was recovered and concentrated to give an orange oil (22.8g, 99% yield).

(iv) Recrystallisation

The crude product from step (iii) was dissolved in hexane (10 ml) andcooled (0-5° C.). The solution was stirred for 2-3 hours. The mixturewas seeded after 1 hour. The material crystallised as a white/yellowsolid which was filtered through pre-cooled apparatus and washed withcold hexane (5 ml) to give 9.4 g at 99% Str. −50% recovery based on %Str.

EXAMPLE 3

(i) Preparation of Weinreb amide 100% Mole Material Source % Str. Weight(g) Wt. (g) MWt. Moles ratio D-2-benzyl- 93.5 21.21 19.83 198.5 0.1  1oxypropionyl chloride N,O-Dimethyl Aldrich 98 9.98  9.78 97.55 0.1  1hydroxyl amine, HCl Pyridine Aldrich 99%+ 15.8 15.64 79.1  0.198 2Dichloro- Fisons 89 + 16 ml methane 1N HCl Rimon 200 ml 0.2  2 Ethylacetate Fisons 100 ml

A solution of pyridine in dichloromethane (16 ml) was added dropwise toa suspension of N,O-dimethylhydroxylamine hydrochloride andD-2-benzyloxypropionyl chloride (prepared by the method of Example 1,stages (i) and (ii)) in dichloromethane (89 ml) at 20-30° C. The mixturewas stirred overnight. The solvent was removed and the residuepartitioned between 1NHCl and EtOAc. The organic phase was recovered andconcentrated to give an oil (22.0 g, 95% yield).

(ii) Preparation of Stock Solution of Grignard:2,4-difluorophenylmagnesium bromide Prepared by the Method Above forExample 2(ii)

(iii) Reaction of Weinreb amide with Grignard 100% Mole Material Source% Str. Weight (g) Wt. (g) MWt. Moles ratio Weinreb Ex. 3(i) 96 15 14.5223 0.065 1 amide 2,4- Ex. 3(ii) 45 ml + 0.072 1.1 + difluornphenylextra based extra as magensium on GC required bromide (2.4 ml) (0.06)THF Fisons 40 ml 1N HCl Rimon 200 ml 0.2  2.63 Ethyl acetate Fisons 50ml

The Weinreb amide was dissolved in the THF. The solution of Grignard wasadded over 20 minutes at 20-30° C. (required slight cooling). Thereaction was stirred for 30 minutes and sampled by GC. The % conversionwas used to calculate an additional charge of Grignard. The additionalGrignard was added and the reaction was stirred for 45 minutes. Thereaction mixture was poured slowly into aq. 1 N HCl at 20-30° C.(required slight cooling). The mixture was extracted with ethyl acetate.The upper organic layer was recovered and concentrated to give an oil17.4 g, 89% yield.

(iv) Recrystallisation

2 g of the crude product from step (c) was dissolved in hexane (1.5 ml)and cooled (0-5° C.). The solution was stirred for 1.5 hours. Themixture was seeded after 1 hour. The material crystallised as awhite/yellow solid which was filtered through pre-cooled apparatus andwashed with cold hexane (0.5 ml) to give 1.2 g at 98% Str. −66% recoverybased on % Str.

What is claimed is:
 1. A process for the preparation of a compound ofFormula (1):

wherein: X¹ and X² are each independently H, Cl or F, provided that atleast one of X¹ and X² is Cl or F; one of R¹ and R² is H and the otheris OH; and R⁵ is an unsubstituted alkyl, comprising the steps: (a)condensing a 2-chloroalkanoic acid with an optionally substituted benzylalcohol to form a 2-(optionally substituted benzyloxy) alkanoic acid;(b) converting the product from step (a) to the corresponding acidchloride; then either: (c) reacting the product of step (b) with acompound of the Formula (2) in the presence of a source of copper (I) togive a compound of Formula (3) wherein one of R³ and R⁴ is H and theother is optionally substituted benzyloxy;

(d) reacting the product of step (b) with a compound of Formula (4):A—NH—B wherein A and B independently represent substituted alkyl,alkoxy, aryl or oxyaryl groups, or are linked to form a heterocyclicring to form an amide, and then reacting the amide with a compound ofFormula (2) to give a compound of Formula (3); and (e) removing theoptionally substituted benzyl group from the compound of Formula (3) byhydrogenation, thereby giving the compound of Formula (1).
 2. A processfor the preparation of a compound of Formula (3):

wherein: X¹ and X² are each independently H, Cl or F, provided that atleast one of X¹ and X² is Cl or F; one of R³ and R⁴ is H and the otheris optionally substituted benzyloxy; R⁵ is an unsubstituted alkyl,preferably a C₁₋₆ alkyl, group; comprising the steps: (a) condensing a2-chloroalkanoic acid with an optionally substituted benzyl alcohol toform a 2-(optionally substituted benzyloxy) alkanoic acid; (b)converting the product from step (a) to the corresponding acid chloride;then either: (c) reacting the product of step (b) with a compound of theFormula (2):

in the presence of a source of copper (I) to give a compound of Formula(3); or (d) reacting the product of step (b) with a compound of Formula(4): A—NH—B wherein A and B independently represent substituted alkyl,alkoxy, aryl or oxyaryl groups, or are linked to form a heterocyclicring to form an amide, and then reacting the amide with a compound ofFormula (2) to give a compound of Formula (3).
 3. A process according toclaim 1, wherein the source of copper (I) employed in step (c) isselected from the group consisting of CuNO₃, CuCN, CuCl, CuBr and Cul.4. A process according to claim 1, wherein the compound of Formula (4)is selected from the group consisting of morpholine, pyrrolidine andN-methoxy-N-methylamine.
 5. A process according to claim 1, wherein X¹and X² are both F.
 6. A process according to claim 1, wherein thecompound of Formula (3) is purified by recrystallisation.
 7. A processaccording to claim 1, wherein R⁵ represents a methyl group.
 8. A processaccording to claim 1, wherein R⁵ is a C₁₋₆ alkyl group.